The endothelial dysfunction associated with cardiovascular risk factors such as hypercholesterolemia, hypertension and aging, results in a predisposition to atherosclerosis. Atherosclerotic lesion formation involves a complex interaction between mononuclear cells and vascular endothelium that leads to the characteristic stages of the human disease can be mimicked in a mouse apoE model of atherosclerosis. Epidemiologic and accumulating experimental evidence indicates that moderate consumption of alcoholic beverages, in particular red wine, decreases the incidence of cardiovascular disease as well as the mortality associated with myocardial infarction. Preliminary data show that (1) polyphenols enhance post-ischemic myocardial function; (2) polyphenols interfere with monocyte adherence to mouse endothelial cells; (3) both alcohol and polyphenols increase the expression of nitric oxide synthases (NOS) mRNA and protein in the vasculature; (4) cells transfected with the full length eNOS promoter respond to both alcohol and polyphenols by increased activity; (5) the bioavailability of.NO may also be increased by induction of superoxide dismutases (SOD); and (6) that the increased bioavailability of .NO may be responsible for the cardiovascular protection associated with moderate alcohol consumption. These data have led to the hypothesis that "alcohol and/or polyphenol induced increase in nitric oxide (.NO) bioavailability is a critical event in the attenuation of the vascular dysfunction and lesion formation in a mouse model of atherosclerosis". This hypothesis will be tested by completion of the following Specific Aims: (1) determining the role of ethanol and polyphenols in attenuating the altered vascular function and development of morphologic lesions in an apolipoprotein E-deficient mouse model of atherogenesis; (2) defining the molecular mechanism(s) of the alcohol and polyphenol-induced increase in NO bioavailability and altered vascular function; and (3) identification of the regulatory region(s) in the promoter and 5' flanking region of the eNOS gene responsive to ethanol and polyphenols and characterization of the transcription factor(s) that mediate the ethanol- and/or polyphenol- induced increased eNOS expression. Completion of these specific aims will provide insight into the mechanisms by which alcohol and polyphenols lead to increased .NO and role that these .NO-dependent mechanisms play in attenuation of vascular dysfunction and lesion formation associated with atherosclerosis.